HPV-SAVE: 9-Valent HPV Vaccine for High-Grade Anal Dysplasia

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Brief Title

HPV-SAVE_Merck_Sub-Study for Preventing Recurrence of HSIL

Official Title

A Multicenter, Randomized Controlled Trial of the Efficacy, Safety and Immunogenicity of HPV Vaccination in Preventing Recurrence of HSIL in HIV-positive MSM

Brief Summary

      Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) worldwide.
      Infection by certain high-risk oncogenic types of HPV (HR-HPV) is the major cause of several
      cancers in men, notably squamous cell carcinoma (SCC) of the anal canal. Rates of anal
      infection with these HR-HPV strains, and the resultant high-grade anal dysplasia and anal
      cancer are much higher in men who have sex with men (MSM) than in the general population.
      Co-infection with human immunodeficiency virus (HIV) further amplifies this burden, making
      the rates of anal SCC in HIV-positive MSM higher than the historic rates of cervical cancer
      prior to the adoption of routine cervical cytology screening. Despite these alarming
      statistics, there are no established protocols for optimal screening and treatment of anal
      HPV and cancer precursors, nor has there been any widespread rollout of organized screening
      programs anywhere in Canada. Further, not only does HPV directly cause significant disease in
      these men, but there is growing epidemiologic evidence that HPV infection may enhance sexual
      transmission of HIV. These significant knowledge gaps translate into fundamental deficiencies
      in care for HIV-positive MSM.

      The HPV Screening and Vaccine Evaluation in MSM (HPV-SAVE) study team was funded by the
      Canadian Institutes of Health Research (CIHR) via its Boys' and Men's Health Team Grant
      Competition. It aims to recruit a large group of MSM from various Ontario and Vancouver
      clinics, in order to carry out a number of different studies. The HPV-SAVE team brings
      together community and internationally-recognized experts in HPV and HIV disease and mucosal
      immunology, to better define the optimal approaches for primary and secondary prevention and
      treatment of HPV-associated anal disease among HIV-positive MSM, and to explore biological
      mechanistic evidence regarding the potential role of HPV as a co-factor for HIV transmission.
      This will yield critical information which can lead to improvement in the health of MSM, and
      will provide a foundation on which to build large-scale screening and treatment trials on a
      national level. A key part of this research program involves an analysis of the potential
      role played by the HPV vaccine in the overall management of HIV-positive MSM.

      Planned vaccine-related projects include:

        -  A mixed-methods analysis of the knowledge, attitudes, and acceptability of HPV
           vaccination amongst HIV-positive MSM, through quantitative (e.g. cross-sectional survey)
           and qualitative (e.g. in-depth interviews) means.

        -  A comprehensive assessment of the 9-valent HPV vaccine in HIV-positive MSM, including
           safety and immunogenicity, as well as its potential role in secondary prevention of
           high-grade anal dysplasia. This is the study on which the current proposal is based.

Detailed Description

      Advances in the treatment of HIV-infected individuals with the advent of the combination
      antiretroviral therapy (cART) era has led to dramatic reductions in mortality and morbidity.
      These dramatic strides in survival within HIV-positive populations have led to a focus on
      longer-term morbidities in these individuals, including malignancies. Indeed, an increase in
      a variety of malignancies in HIV-infected individuals has been noted in the cART era. Amongst
      these are cancers associated with HPV, responsible for the vast majority of cervical cancers
      (itself a well-established acquired immune deficiency syndrome (AIDS)-defining illness), and
      40-90% of anal, vulvar, vaginal, penile, and oropharyngeal cancers. More specifically, a
      recent meta-analysis indicates that the overall prevalence of HPV in anal carcinoma is
      approximately 84%, with HPV type 16 being isolated in 73% of all cases, making it the most
      prevalent type implicated in anal carcinoma.

      Though infrequent at a rate of one per 100 000, squamous cell anal carcinoma is on the rise
      in the general population. It occurs at significantly higher rates in HIV-positive men -
      particularly among MSM - with an estimated rate of 60 to 160 per 100 000. A recent study of
      thirteen North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) with
      over 34,000 HIV-infected patients, found that anal cancer rates were highest in HIV-infected
      MSM, with a rate of 131 per 100,000 person years. In fact, rates of anal cancer among
      HIV-infected MSM are comparable to rates of cervical cancer in women prior to the adoption of
      routine screening for cervical dysplasia. In addition to its etiologic association with HPV,
      anal cancer shares many similarities with cervical cancer. Both are squamous cell cancers
      occurring at the squamo-columnar junction, and both likely arise from histologically-similar,
      dysplastic precursor lesions. It is postulated that a critical step in anal cancer
      carcinogenesis is the establishment of persistent infection (conventionally defined as
      greater than six or twelve months) with oncogenic HPV in the anal canal. Though the majority
      of HPV infections are considered transient and will eventually clear even in HIV-positive
      individuals, HIV-positive individuals have higher rates of persistent infection, especially
      with oncogenic HPV types.

      Of the greater than 170 HPV types, over 30 favour the anogenital area, and on the basis of
      epidemiologic and phylogenetic data, these have been classified by the International Agency
      for Research on Cancer (IARC).

      The vast majority of anal cancers (as well as cervical cancers) are caused by two high-risk
      HPV types: HPV type 16 and HPV type 18, felt to be responsible for 66% and 5% of anal
      cancers, respectively. However, a recent study from France examining the distribution of HPV
      types in cases of anal cancer found even more dramatic results: HPV was found in 96.7% of all
      cases, with HPV-16 being the most prevalent type (75%), with other high risk types (HPV-18,
      -52, -33, and -51) found in 4% to 6% of cases. Further, HPV-16 and -18 - either alone or in
      combination - were found in over 78% of cases. HPV lesions caused by low-risk types include
      condylomata (or commonly known as 'genital warts'), of which 90% are caused by HPV types 6
      and 11.

      Prevention strategies for anal cancers have emerged that are analogous to strategies used in
      cervical cancer screening, that rely on a combination of cytology (Papanicolaou, or Pap
      smear) and high-resolution anoscopy (HRA; analogous to colposcopy), both of which screen for
      high-grade anal intraepithelial neoplasia (HGAIN; typically graded as anal intraepithelial
      neoplasia (AIN) AIN-2 or -3). Despite the clear evidence indicating the benefit of screening
      and treatment procedures in cervical cancer screening, no large rigorous studies have been
      performed to assess the performance of such strategies in anal cancer screening in either men
      or women.

      In addition to the scant literature on the efficacy of screening programs for anal cancer and
      HPV in all men - but particularly those who are HIV-positive - there remains an even greater
      paucity of data on issues surrounding primary prevention of HPV. The HPV quadrivalent
      recombinant vaccine, or Gardasil®, protects against HPV types 6 and 11, which are the most
      common types implicated in condylomata acuminata (anogenital warts), as well as the most
      common oncogenic strains, types 16 and 18. The use of this vaccine has been shown to prevent
      persistent cervical HPV infection caused by vaccine types in women, as well as preventing
      nearly all high grade genital lesions in women - the latter of which are considered precursor
      lesions to invasive cancers. Additionally, a retrospective pooled analysis of two large
      efficacy trials of quadrivalent HPV vaccine has also demonstrated a treatment effect from HPV
      vaccine in preventing recurrences of previously treated high grade cervical disease.

      Few studies have been done on the use of the quadrivalent HPV vaccine in men; there has only
      been one study examining the use of the HPV vaccine in HIV-positive men, and this study found
      the vaccine to be safe and immunogenic. Overall, these studies have shown promise,
      demonstrating a reduction in vaccine-type genital lesions in young men who were vaccinated
      versus those receiving placebo, evidence of protection against HGAIN in MSM, and a 50%
      reduction rate in HGAIN recurrence in MSM previously treated for dysplastic lesions. This
      latter study lays the foundation of the currently proposed study. However, the role of the
      HPV vaccine in secondary prevention of HGAIN has not been examined in a systematic,
      prospective way. Given the unacceptably high rates of HGAIN recurrence in those having
      undergone ablative therapy (from 62% to 91% within two years in HIV-positive MSM), exploring
      this potentially novel benefit of the HPV vaccine is certainly warranted and could
      potentially change the way clinicians address HPV-related disease in this high-risk group.

      Until recently there existed no standard recommendation for the use of HPV vaccinations in
      males, regardless of HIV serostatus; however, these studies have prompted the Centres for
      Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) to
      recommend that boys be routinely vaccinated for HPV beginning at age 11 or 12. Canada's
      National Advisory Committee on Immunizations (NACI) went further, recommending vaccination in
      all males between 9 and 26 years of age, as well as any MSM 9 years of age or older.

      Gardasil-9 is a novel, 9-valent HPV recombinant vaccine, which expands the coverage of
      oncogenic HPV types, with the addition of HPV types 31, 33, 45, 52, and 58 to the existing
      quadrivalent vaccine types. The addition of these five oncogenic types is estimated to
      improve cancer coverage to 90% (versus 70% for the quadrivalent vaccine). With its expanded
      coverage of oncogenic HPV types, its proven efficacy in primary prevention and its potential
      role in mitigating HGAIN recurrences - all coupled with the disproportionate burden of
      HPV-related anal cancers borne by HIV-positive MSM - it is critical that its use be
      comprehensively assessed in this very high risk population

Study Phase

Phase 2

Study Type


Primary Outcome

The proportion of participants in each arm with biopsy-proven HGAIN (AIN-2/3).

Secondary Outcome

 The geometric mean titres (GMT) of antibody to each vaccine type above a pre-specified, validated cut-off. F


Anal Intraepithelial Neoplasia


9-valent HPV vaccination

Study Arms / Comparison Groups

 Immediate Vaccination
Description:  Administration of dose #1 of 9-valent HPV vaccination will be given at baseline visit, dose #2 at month 2, and dose #3 at month 6.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

September 1, 2022

Completion Date

May 1, 2026

Primary Completion Date

March 1, 2026

Eligibility Criteria

        Subject Inclusion Criteria

          1. Males, aged ≥ 18 years at baseline;

          2. Physician or laboratory documentation of HIV-1 infection (enzyme-linked immunosorbent
             assay [ELISA] and Western Blot);

          3. AIN-2 or -3 found on biopsy of anal canal lesion(s), and willingness of the subject to
             undergo ablative therapy which is standard of care in most screening clinics;

          4. History of any sexual activity with men, or both men and women, where sexual activity
             is defined as oral, vaginal, or anal intercourse;

          5. For those on cART, the participant must be on a stable regimen (i.e. virologically
             suppressed with HIV-1 ribonucleic acid (RNA) below the assay's limit of detection for
             minimum six months). This will minimize confounding from dramatic shifts in viral load
             and/or cluster of differentiation 4 (CD4) count;

          6. For those individuals that are not on cART, there must be no immediate plans to
             initiate cART in the next six months. There will be no lower limit cut-off for CD4

          7. An ability to give informed consent;

          8. An ability to attend clinic for all study visits.

        Subject Exclusion Criteria

          1. Known hypersensitivity to any component of the HPV vaccine (e.g. Saccharomyces
             cerevisiae yeast, Amorphous Aluminium Hydroxyphosphate Sulfate adjuvant);

          2. Current or prior history of cancer of the anogenital regions (e.g. penile, anal, or
             rectal) or of the oropharyngeal area (e.g. oral cavity, upper airway).

          3. Previous HPV immunization.




18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Irving Salit, MD, 416-340-3697, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

University Health Network, Toronto


 Merck Sharp & Dohme LLC

Study Sponsor

Irving Salit, MD, Principal Investigator, Toronto General Hospital, University Health Network

Verification Date

June 2022